Novel mutations in the TCIRG1 gene encoding the a3 subunit of the vacuolar proton pump in patients affected by infantile malignant osteopetrosis.

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Fifty percent of the infantile malignant osteopetrosis (IMO) cases reported in the literature present mutations in the TCIRG1 gene encoding the 116-kDa osteoclast specific subunit of the vacuolar proton ATPase (ATP6I). In this study, we identified four novel mutations in a series of six IMO patients. All of these mutations correspond to single nucleotide changes and affect splice acceptor or donor sites, resulting in aberrant transcription products. We report also a missense mutation, G405R, previously described in several Costa Rican patients. This independent finding suggests that the highly conserved residue at amino acid 405 plays a critical role in the a3 subunit function. Finally, the results of this study were used to provide a prenatal diagnosis to one of the families.